Open Access Review of Lithium Effects on Brain and Blood

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Abstract:

Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3 (GSK3). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6‐1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5‐2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It “cures” a third of the patients with manic depression, improves the lives of about a third, and is ineffective in about a third. Recent studies suggest that some anticonvulsants (i.e., valproate, carbamapazine, and lamotrigene) may be useful in patients that do not respond to lithium. Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions. Clinical trials assessing the effects of lithium are under way. A recent clinical trial suggests that lithium stops the progression of ALS.

Keywords: Blood effects; Brain effects; Lithium; Mechanisms of effects; Mood disorders

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/096368909X471251

Affiliations: W. M. Keck Center for Collaborative Neuroscience, Rutgers, State University of New Jersey, Piscataway, NJ, USA. wisey@mac.com

Publication date: September 1, 2009

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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